Evidence for a Common Mechanism of SIRT1 Regulation by Allosteric Activators
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Open Access
- 8 March 2013
- journal article
- other
- Published by American Association for the Advancement of Science (AAAS) in Science
- Vol. 339 (6124), 1216-1219
- https://doi.org/10.1126/science.1231097
Abstract
A molecule that treats multiple age-related diseases would have a major impact on global health and economics. The SIRT1 deacetylase has drawn attention in this regard as a target for drug design. Yet controversy exists around the mechanism of sirtuin-activating compounds (STACs). We found that specific hydrophobic motifs found in SIRT1 substrates such as PGC-1α and FOXO3a facilitate SIRT1 activation by STACs. A single amino acid in SIRT1, Glu230, located in a structured N-terminal domain, was critical for activation by all previously reported STAC scaffolds and a new class of chemically distinct activators. In primary cells reconstituted with activation-defective SIRT1, the metabolic effects of STACs were blocked. Thus, SIRT1 can be directly activated through an allosteric mechanism common to chemically diverse STACs.Keywords
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